This invention relates to a method for the treatment of herpesviruses and, more particularly, to the use of N-alkyl derivatives of 1,5-dideoxy-l,5-imino-D-glucitol for inhibiting viruses of the Herpesviridae family, e.g., herpes simplex virus (HSV), varicella-zoster virus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV).
The herpesviruses are a family of DNA viruses which have a special affinity for cells of ectodermal origin and tend to promote latent infections. Herpesviruses are a maJor cause of disease in humans. Coincident infection by these viruses also is common in patients having acquired immune deficiency syndrome (AIDS).
Various drugs and other therapeutic treatments have been indicated for use against herpesviruses. The use of various purine, pyrimidine and pyrrolidine derivatives for this purpose, e.g., the purine and pyrimidine acyclic nucleosides, is particularly noteworthy. Two such compounds are 9-[(2-hydroxyethoxy)methyl]-guanine or acyclovir and the analogous 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) or ganciclovir. The use of acyclovir as an antiviral for HSV is described, for example, by Schaeffer, Nature 272, 583(1978); Balfour, Ann. Rev. Med. 35, 279-291 (198); and in U.S. Pat. Nos. 4,199,574 and 4,758,572. Use of ganciclovir for treatment of CMV in AIDS patients, especially against CMV retinitis, is disclosed, for example, by Bach et al., Ann. Inter. Med. 103, 381-382 (1985); Masur et al., Ibid. 104, 41-44 (1986); and The Collaborative DHPG Treatment Study Group, N. Engl. J. Med. 314, 801-805 (1986). The in vitro activity of acyclovir against CMV infections in a plaque reduction assay is described by Tyms et al., J. Antimicrobial Chemotherapy 8, 65-72 (1981). The antiviral activity of ganciclovir against CMV infection in a cell culture model is described by Tyms et al., J. Gen. Virology 68, 1563-1573 (1987).
Another type of compound reported to be useful against herpesviruses is the glycosylation inhibitor 2-deoxy-D-glucose. The activity of this compound against HSV is described, for example, by Courtney et al., Virology 52, 447-455 (1973); Blough, J. Amer. Med. Assn. 241(26), 2798-2801 (1979); Blough et al., Biochem. Biophys. Res. Commun. 141(1), 33-38 (1986): and in U.S. Pat. No. 4,315,001.
Recently, certain plant alkaloid inhibitors of glucosidase activity which were found to block the growth of the AIDS-associated virus HIV were also suggested as potentially active against cytomegalovirus replication. See Tyms et al., Lancet, Oct. 31, 1987, pp. 1025-1026. The reported alkaloids were castanospermine (CAST), dihydroxymethyldihydroxypyrrolidine (DMDP) and 1deoxynoirimycin (DNJ). The latter compound is alternatively named 1,5-dideoxy-l,5-imino-Dglucitol.
The use of CAST, DMDP, DNJ and the N-methyl derivative of DNJ against AIDS-associated retroviruses is further disclosed in PCT Inter. Appln. WO 87/03903, published July 2, 1987.
The use of the N-butyl derivative of DNJ for inhibition of human immunodeficiency virus (HIV) is disclosed by Fleet et al., FEBS Lett. 237, 128-132 (1988) and in copending applications Ser. No. 166,065, filed Mar. 9, 1988 and Ser. No. 248,461, filed Sept. 23, 1988. Its synthesis and use for various other therapeutic indications is described in U.S. Pat. Nos.4,182,767 and 4,639,436. The latter patent also discloses methods for making other N-alkyl derivatives of DNJ, e.g., the N-methyl and N-hexyl derivatives.
Further background information concerning the effects on virus multiplication by inhibitors of glycosylation can be had by reference to the recent review article by Datema et al., Pharmac. Ther. 33, 221-286 (1987). The use of oligosaccharide processing inhibitors CAST, DNJ, and similar agents against DNA viruses such as HSV CMV, EBV and varicella-zoster virus is described at pages 262-269.